SUPPORTING INFORMATION

Transcription

1 Synthesis and Biological Evaluation of Direct Thrombin Inhibitors Bearing 4-(Piperidin-1- yl)pyridine at the P1 Position with Potent Anticoagulant Activity Modesto de Candia, Filomena Fiorella,,# Gianfranco Lopopolo,, Andrea Carotti, Maria Rosaria Romano, Marcello Diego Lograno, Sophie Martel, Pierre-Alain Carrupt, Benny D. Belviso, Rocco Caliandro and Cosimo Altomare*, Dipartimento di Farmacia - Scienze del Farmaco, University of Bari Aldo Moro, Via E. Orabona 4, Bari, Italy Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, via del Liceo 1, Perugia, Italy School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest- Ansermet 30, CH-1211 Geneva 4, Switzerland Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Amendola 122/o, Bari, Italy SUPPORTING INFORMATION Analytical and spectral data of intermediates and tested compounds.. 2 X-ray crystal data of 13b. 13 1

2 Analytical and spectral data of intermediates and tested compounds Melting points were determined by using the capillary method on a Stuart Scientific SMP3 electrothermal apparatus and are uncorrected. Elemental analyses (C, H, N) were performed on an Euro EA3000 analyzer (Eurovector, Milan, Italy) using the Analytical Laboratory Service of the Department of Pharmacy - Drug Sciences of the University of Bari (Italy), and the results agreed to within ±0.40% of the theoretical values. Mass spectra were recorded on Agilent GC-MS IR spectra were recorded using KBr disks on a Perkin Elmer Spectrum One FT-IR spectrophotometer (Perkin Elmer Ltd., Buckinghamshire, UK), and the most significant absorption bands are listed. 1 H NMR spectra were recorded at 300 MHz on a Varian Mercury 300 instrument. Chemical shifts are expressed in δ and the coupling constants J in hertz (hz). The following abbreviations are used: s, singlet; d, doublet; dd, doublet-doublett; t, triplet; m, multiplet. Signal due to NH and OH protons were located by deuterium exchange with D 2 O. Chromatographic separations were performed on silica gel 60 for column chromatography (Merck mesh, or alternatively mesh for flash chromatography). Unless otherwise stated, starting materials, and all chemicals and solvents as well, were purchased from Sigma-Aldrich. Several compounds were synthesized according to known procedures with slight modifications; their melting points and spectral data were in full agreement with those reported in literature, and no effort was made at this stage to optimize the yields. N-{3-[(4-fluorobenzyl)oxy]phenyl}-1-pyrimidin-2-ylpiperidine-4-carboxamide (11). Compound 11 was prepared starting from 1-(pyrimidin-2-yl)piperidine-4-carboxylic acid 10a and 3-[(4-fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a. Brown solid (10% yield). Mp C. IR (KBr) 3265, 1651, 1588, 1547, 1510, 1084 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.33 (br, 2 H), (m, 3 H), 7, (m, 4 H), (m, 2 H), 5.02 (s, 2 H), (m, 2 H), 2.92 (d, J = 11.5 Hz, 1 H), 2.88 (d, J = 12 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H); ESIMS m/z 407 (MH + ); Anal. Calcd. for C 23 H 23 N 4 O 2 F H 2 O: C, 65.08; H, 5.94; N, 13.20%. Found: C, 65.12; H, 6.19; N, 12.98%. N-(3-(4-fluorobenzyloxy)phenyl)-1-(pyridin-2-yl)piperidine-4-carboxamide (12). Compound 12 was obtained as brown solid, starting from 1-(pyridin-2-yl)piperidine-4-carboxylic acid 10b and 3-[(4-fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (15% yield). Mp C. IR (KBr) 3232, 1649, 1596, 1489, 1439, 1226, 1207, 1154, 1011 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.89 (s, 1 H), 8.08 (d, J = 3.0 Hz, 1 H),

3 7.39 (m, 4 H), (m, 4 H), 6.82 (d, J = 8.5 Hz, 1 H), 6.65 (d, J = 7.0 Hz, 1 H), (m, 1 H), 5.01 (s, 2 H), 4.33 (d, J = 13.0 Hz, 2 H), 2.83 (d, J = 12.0 Hz, 1 H), 2.79 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 407 (MH + ); Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.19; H, 6.12; N, 10.42%. N-{3-[(4-fluorobenzyl)oxy]phenyl}-1-(4-nitrophenyl)piperidine-4-carboxamide (14). Compound 14 was obtained as yellow solid, starting from 1-(4-nitrophenyl)piperidine-4-carboxylic acid 10d and 3-[(4-fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (20% yield). Mp C. IR (KBr) 3240, 1632, 1599, 1318, 1203, 1155, 1114 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) δ 8.13 (d, J = 9.0 Hz, 2 H), 7.46 (br, 1 H), 7.40 (dd, J 1 = 9.0, J 2 = 3.0 Hz, 2 H), 7.21 (dd, J 1 = 8.0, J 2 = 2.0 Hz, 1 H), 7.15 (t, J = 2.0 Hz, 1 H), 7.06 (t, J = 9.0 Hz, 1 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.84 (d, J = 9.0 Hz, 2 H), 6.73 (d, J = 8.0, Hz, 1 H), 6.47 (s, 1 H), 5.02 (s, 2 H), (m, 2 H), (m, 2 H), (m, 1 H), (m, 4 H). ESIMS m/z 448 (MH + ). N-[3-(benzyloxy)phenyl]-1-pyridin-4-ylpiperidine-4-carboxamide (18). Compound 18 was obtained as brown solid, starting from 1-(pyrimidin-4-yl)piperidine-4-carboxylic acid 10c and benzyloxyaniline, following the general procedure reported for compound 13a (21% yield). Mp C dec. IR (KBr) 1667, 1605, 1557, 1447, 1209, 1027, 998, 805, 763, 739, 697 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.91 (s, 1 H), 8.12 (d, J = 5.5 Hz, 2 H), (m, 6 H), (m, 2 H), 6.81 (d, J = 6.0 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.04 (s, 2 H), 3.97 (d, J = 13.5 Hz, 2 H), 2.88 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 11.0 Hz, 1 H), (m, 1 H), 1.82 (d, J = 11.0 Hz, 2 H), (m, 2 H). ESIMS m/z 388 (MH + ). Anal. Calcd. For C 24 H 25 N 3 O 2 H 2 O: C, 71.09; H, 6.71; N, 10.36%; found: C, 70.62; H, 6.67; N, 10.21%. N-{3-[(3-fluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (13b). Compound 13b was obtained as brown solid, starting from acid 10c and 3-[(3- fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (yield 59%). Mp C. IR (KBr) 3450, 1666, 1604, 1515, 1481, 1209, 1033, 805. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.12 (d J = 5.5 Hz, 2 H), (m, 2 H), (m, 5 H), 6.81 (d, J = 5.5 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.07 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.86 (d, J = 12.0 Hz, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.15; H, 6.09; N, 10.40%. N-{3-[(2-fluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (13c). 3

4 Compound 13c was obtained as pale brown solid, starting from acid 10c and 3-[(2- fluorobenzyl)oxy]aniline, following general the procedure reported for compound 13a (42% yield). Mp C. IR (KBr) 3429, 2952, 1669, 1601, 1556, 1448, 1206, 1033, 997, 807, 767 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.11 (d, J = 5.5 Hz, 2 H), 7.52 (m, 1 H), 7.38 (s, 2 H), (m, 4 H), 6.70 (d. J = 6.5 Hz, 2 H), 6.68 (d, J = 8.5 Hz, 1 H), 5.07 (s, 2 H), 4.0 (d, J = 12.0 Hz, 2 H), 2.87 (m, 2 H), 2.58 (t, J = 13.0 Hz, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH+). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.22; H, 5.95; N, 10.42%. N-{3-[(2,4-difluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (13d). Compound 13d was obtained as pale brown solid, starting from acid 10c and 3-[(2,4- difluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (36% yield). Mp 223 C-dec. IR (KBr) 3447, 1604, 1448, 1208, 805 cm -1 ; 1 H NMR (300 MHz, DMSOd 6 ) δ 9.94 (s, 1 H), 8.12 (d, J = 5.0 Hz, 2 H), 7.58 (d, J = 7.0 Hz, 2 H), 7.39 (s, 1 H), 7.29 (t, J = 8.0 Hz, 1H), (m, 3 H), 6.81 (d, J = 5.0 Hz, 2 H), 6.68 (d, J = 8.0 Hz, 1 H), 5.04 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.86 (dd, J = 12.0 Hz, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 424 (MH + ). Anal. Calcd. for C 24 H 23 N 3 O 2 F 2 : C, 68.07; H, 5.47; N, 9.92%. Found: C, 68.25; H, 5.65; N, 10.02%. N-{3-[(3,5-difluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (13e). Compound 13e was obtained as pale brown solid, starting from acid 10c and 3-[(3,5- difluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (52% yield). Mp 120 C dec. IR (KBr) 1664, 1601, 1557, 1448, 1383, 1213, 1117, 998, 807, 775 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.95 (s, 1 H), 8.13 (d, J = 5.5 Hz, 2 H), 7.41 (s, 1 H), (m, 4 H), (m, 3 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.08 (s, 2 H), 3.98 (d, J = 13.0 Hz, 2 H), 2.93 (d, J = 12.0 Hz, 1 H), 2.89 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 424 (MH + ). Anal. Calcd. for C 24 H 23 N 3 O 2 F 2 : C, 68.07; H, 5.47; N, 9.92%. Found: C, 68.12; H, 5.35; N, 9.98%. N-{3-[(4-chlorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (19a). Compound 19a was obtained as brown solid, starting from acid 10c and 3-[(4- chlorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (37% yield). Mp C. IR (KBr) 3445, 1668, 1604, 1555, 1493, 1209, 805. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), (m, 4 H), (m, 2 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.65 (m, J = 8.0 Hz, 1 H), 5.04 (s, 2 H), 3.96 (m, J = 7.5 Hz, 2 H),

5 (m, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 422 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 Cl: C, 68.32; H, 5.73; N, 9.96%. Found: C, 68.51; H, 5.92; N, 10.01%. N-{3-[(3-chlorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (19b). Compound 19b was obtained as brown solid, starting from acid 10c and 3-[(3- chlorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (55% yield). Mp C. IR (KBr) 3425, 2926, 1684, 1600, 1206, 996, 814, 806, 781. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.94 (s, 1 H), 8.12 (d, J = 6.0 Hz, 2 H), 7.48 (s, 1 H), (m, 4 H), (m, 2 H), 6.81 (d, J = 6.0 Hz, 2 H), 6.66 (d, J = 8.5 Hz, 1 H), 5.06 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.86 (d, J = 12.0 Hz, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 422 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 Cl: C, 68.32; H, 5.73; N, 9.96%. Found: C, 68.35; H, 5.82; N, 9.95%. N-{3-[(4-bromobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (20a). Compound 20a was obtained as brown solid, starting from acid 10c and 3-[(4- bromobenzyl)oxy]aniline, following the general procedure reported for compound 13a (55% yield). Mp C. IR (KBr) 3433, 2926, 1669, 1604, 1554, 1287, 1208, 998, 805 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.11 (d, J = 6.0 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H), (m, 3 H), (m, 2 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.66 (d, J = 7.5 Hz, 1 H), 5.02 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), (m, 2 H), 2.88 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 466 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 Br: C, 61.81; H, 5.19; N, 9.01%. Found: C, ; H, 5.22; N, 9.11%. N-{3-[(3-bromobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (20b). Compound 20b was obtained as brown solid, starting from acid 10c and 3-[(3- bromobenzyl)oxy]aniline, following the general procedure reported for compound 13a (45% yield). Mp C. IR (KBr) 1666, 1605, 1555, 1512, 1447, 1209, 1031, 998, 874, 804. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), 7.62 (s, 1 H), (m, 4 H), (m, 2 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.06 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.89 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), 1.82 (m, 2 H), (m, 2 H). ESIMS m/z 466 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 Br: C, 61.81; H, 5.19; N, 9.01%. Found: C, ; H, 5.12; N, 9.11%. N-{3-[(4-nitrobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (21a). 5

6 Compound 21a was obtained as orange solid, starting from acid 10c and 3-[(4- nitrobenzyl)oxy]aniline, following the general procedure reported for compound 13a (55% yield). Mp 129 C-dec. IR (KBr) 3446, 2927, 1635, 1604, 1542, 1518, 1345, 1203, 998, 806, 736 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.86 (s, 1 H), 8.19 (d, J = 9.0 Hz, 2 H), 8.11 (d, J = 5.0 Hz, 2 H), 7.67 (d, J = 9.0 Hz, 2 H), 7.44 (s, 1 H), (m, 2 H), 6.80 (d, J = 5.0 Hz, 2 H), 6.65 (d, J = 7.5 Hz, 1 H), 5.19 (s, 2 H), 3.98 (d, J = 13.0 Hz, 1 H), 3.94 (d, J = 13.0 Hz, 1 H), 2.99 (d, J = 12.0 Hz, 1 H), 2.94 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 433 (MH + ). Anal. Calcd. for C 24 H 24 N 4 O 4 : C, 66.65; H, 5.59; N, 12.96%. Found: C, 66.72; H, 5.75; N, 12.98%. N-{3-[(3-nitrobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (21b). Compound 21b was obtained as pale brown solid, starting from acid 10c and 3-[(3- nitrobenzyl)oxy]aniline, following the general procedure reported for compound 13a (28% yield). Mp C. IR (KBr) 1664, 1603, 1531, 1446, 1353, 1211, 1151, 1102, 999, 876, 807, 730 cm - 1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.94 (s, 1 H), 8.28 (s, 1 H), 8.18 (d, J = 8.5 Hz), 8.12 (d, J = 6.0 Hz, 3 H), 7.89 (d, J = 7.5 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.44 (s, 1 H), (m, 2 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.21 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.88 (d, J = 11.0 Hz, 1 H), 2.84 (d, J = 11.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H).. ESIMS m/z 433 (MH + ). Anal. Calcd. for C 24 H 24 N 4 O 4 : C, 66.65; H, 5.59; N, 12.96%. Found: C, 66.71; H, 5.72; N, 13.01%. N-(3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-1-pyridin-4-ylpiperidine-4-carboxamide (22a). Compound 22a was obtained as pale brown solid, starting from acid 10c and 3-[(4- methylsulfonylbenzyl)oxy]aniline, following the general procedure reported for compound 13a (32% yield). Mp C. IR (KBr) 3443, 3378, 2924, 1667, 1644, 1603, 1542, 1207, 1146, 1088, 1030, 954, 804, 771 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.95 (s, 1 H), 8.10 (d, J = 6.0 Hz, 2 H), (m, 2 H), (m, 2 H), 7.43 (s, 1 H), (m, 2 H), 6.87 (d, J = 5.5 Hz, 2 H), 6.69 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 4.02 (d, J = 12.0 Hz, 2 H), 3.22 (s, 3 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 466 (MH + ). Anal. Calcd. for C 25 H 27 N 3 O 4 S: C, 64.50; H, 5.85; N, 9.03%. Found: C, 64.57; H, 5.92; N, 9.21%. N-(3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-1-pyridin-4-ylpiperidine-4-carboxamide (22b). Compound 22b was obtained as pale brown solid, starting from acid 10c and 3-[(3- methylsulfonylbenzyl)oxy]aniline, following the general procedure reported for compound 13a (30% yield). Mp C. IR (KBr) 1633, 1605, 1557, 1448, 1299, 1209, 1146, 9996, 805, 765 6

7 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.94 (s, 1 H), 8.12 (d, J = 6.0 Hz, 2 H), 7.99 (s, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.44 (s, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.70 (d, J = 8.0 Hz, 1 H), 5.17 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 3.21 (s, 3 H), 2.88 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 466 (MH. Anal. Calcd. for C 25 H 27 N 3 O 4 S: C, 64.50; H, 5.85; N, 9.03%. Found: C, 64.62; H, 5.92; N, 9.11%. N-(3-{[2-(methylsulfonyl)benzyl]oxy}phenyl)-1-pyridin-4-ylpiperidine-4-carboxamide (22c). Compound 22c was obtained as pale brown solid, starting from acid 10c and 3-[(2- methylsulfonylbenzyl)oxy]aniline, following the general procedure reported for compound 13a (30% yield). Mp C. IR (KBr) 3436, 1639, 1600, 1538, 1195, 1153, 1084, 806 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.11 (d, J = 5.0 Hz, 2 H), (m, 2 H), 7.29 (t, J = 8.0 Hz, 1 H), (m, 2 H), 7.02 (d, J = 7.5 Hz, 1 H), 6.94 (t, J = 7.5 Hz, 1 H), 6.81 (d, J = 5.0 Hz, 2 H), 6.65 (d, J = 7.5 Hz, 1 H), 4.99 (s, 2 H), 3.97 (d, J = 13.0 Hz, 1 H), 3.80 (s, 3H), (m, 1 H), 2.86 (d, J = 13.0 Hz, 1 H), 2.84 (d, J = 13.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 466 (MH. Anal. Calcd. for C 25 H 27 N 3 O 4 S: C, 64.50; H, 5.85; N, 9.03%. Found: C, 64.61; H, 6.00; N, 9.11%. N-{3-[(4-trifluoromethylbenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (23a). Compound 23a was obtained as orange solid, starting from acid 10c and 3-[(4- trifluoromethylbenzyl)oxy]aniline, following general the procedure reported for compound 13a (55% yield). Mp C. IR (KBr) 3437, 2960, 1665, 1606, 1556, 1448, 1212, 1027, 999, 806. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), 7.36 (s, 1 H), (m, 2 H), 6.98 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 6.5 Hz, 2 H), (m, 2 H), (m, 2 H), 5.08 (s, 2 H), 4.87 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.87 (dd, J = 12.0 Hz, 2 H), 2.83 (dd, J = 12.0 Hz, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 403 (MH + ). Anal. Calcd. for C 23 H 24 N 3 O 2 F 3 : C, 65.92; H, 5.31; N, 9.23%. Found: C, 66.01; H, 5.32; N, 9.32%. N-{3-[(4-aminobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (24a). Compound 24a was obtained as dark brown solid, starting from compound 21a, by reduction with Raney-Ni and hydrazine hydrate, as reported in the synthesis of compound 15 (75% yield). IR (KBr) 3435, 1660, 1550, 1211, 1025, 770. cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.86 (s, 1 H), 8.11 (d, J = 5.0 Hz, 2 H), 7.44 (s, 1 H), (m, 2 H), 7.07 (d, J = 7.5 Hz, 2 H), 6.80 (d, J = 5.0 Hz, 2 H), 6.65 (d, J = 7.5 Hz, 1 H), 6.58 (d, J = Hz, 2 H), 5.19 (s, 2 H), 3.98 (d, J =

8 Hz, 1 H), 3.94 (d, J = 13.0 Hz, 1 H), 2.99 (d, J = 12.0 Hz, 1 H), 2.94 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 403 (MH + ). Anal. Calcd. for C 24 H 26 N 4 O 2 : C, 71.62; H, 6.51; N, 13.92%. Found: C, 71.77; H, 6.60; N, 13.94%. N-{3-[(3-aminobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (24b). Compound 24b was obtained as dark brown solid, starting from compound 21b, by reduction with Raney-Ni and hydrazine hydrate, as reported in the synthesis of compound 15 (85% yield). Mp 204 C (dec)-210. IR (KBr) 3437, 1665, 1606, 1556, 1449, 1378, 1212, 1027, 1000, 880, 807, 777, 699 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), 7.36 (s, 1 H), (m, 2 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.81 (d, J = 6.5 Hz, 2 H), (m, 2 H), (m, 2 H), 5.08 (s, 2 H), 4.87 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.88 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), 1.82 (d, J = 11.0 Hz, 2 H), (m, 2 H). ESIMS m/z 403 (MH + ). nal. Calcd. for C 24 H 26 N 4 O 2 : C, 71.62; H, 6.51; N, 13.92%. Found: C, 71.74; H, 6.62; N, 13.90%. N-[3-({4-[(dimethylamino)methyl]benzyl}oxy)phenyl]-1-pyridin-4-ylpiperidine-4-carboxamide (25a). Compound 25a was obtained as orange solid, starting from acid 10c and 3-[(4- dimethylaminomethylbenzyl)oxy]aniline, following the general procedure reported for compound 13a (55% yield). Mp C. IR (KBr) 3429, 2924, 1667, 1604, 1556, 1208, 1108, 1028, 997, 874, 804 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.92 (s, 1 H), 8.12 (d, J = 5.5 Hz, 2 H), (m, 5 H), (m, 3 H), 6.81 (d, J = 5.5 Hz, 2 H), 5.06 (s, 2 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.88 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 445 (MH + ). Anal. Calcd. for C 27 H 32 N 4 O 2 : C, 72.94; H, 7.26; N, 12.60%. Found: C, 73.01; H, 7.30; N, 12.78%. N-{3-[(4-methoxybenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (26a). Compound 26a was obtained as pale brown solid, starting from acid 10c and 3-[(4- methoxybenzyl)oxy]aniline, following the general procedure reported for compound 13a (45% yield). Mp C. IR (KBr) 3434, 1666, 1604, 1555, 1250, 1209, 1024, 805 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), (m, 5 H), (m, 2 H), 6.81 (d, J = 6.5 Hz, 2 H), 6.65 (d, J = 8.0 Hz, 1 H), 5.04 (s, 2 H), 4.00 (s, 3 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), 1.81 (m, 2H), (m, 2H). ESIMS m/z 418 (MH + ). Anal. Calcd. for C 25 H 27 N 3 O 3 : C, 71.92; H, 6.52; N, 10.06%. Found: C, 72.12; H, 6.59; N, 10.20%. 8

9 N-{3-[(3-methoxybenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (26b). Compound 26b was obtained as pale brown solid, starting from acid 10c and 3-[(3- methoxybenzyl)oxy]aniline, following the general procedure reported for compound 13a (55% yield). Mp C. IR (KBr) 3450, 1666, 1604, 1515, 1481, 1209, 1033, 805 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.12 (d J = 5.5 Hz, 2 H), (m, 2 H), (m, 5 H), 6.81 (d, J = 5.5 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1 H), 5.07 (s, 2 H), 4.00 (s, 3 H), 3.97 (d, J = 13.0 Hz, 2 H), 2.86 (d, J = 12.0 Hz, 2 H), (s, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 418 (MH + ). Anal. Calcd. for C 25 H 27 N 3 O 3 : C, 71.92; H, 6.52; N, 10.06%. Found: C, 71.99; H, 6.59; N, 9.98%. N-{3-[(2-methoxybenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (26c). Compound 26c was obtained as pale brown solid, starting from acid 10c and 3-[(3- methoxybenzyl)oxy]aniline, following the general procedure reported for compound 13a (37% yield). Mp 205 C-dec. IR (KBr) 3445, 1665, 1605, 1555, 1446, 1210, 1024, 875, 805, 755 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.93 (s, 1 H), 8.11 (d, J = 6.0 Hz, 2 H), 7.52 (m, J = 7.5 Hz, 1 H), 7.38 (s, 2 H), (m, 4 H), 6.70 (d, J = 6.0 Hz, 2 H), 6.68 (d, J = 8.5 Hz, 1 H), 5.07 (s, 2 H), 4.00 (d, J = 12.0 Hz, 2 H), 3.98 (s, 3 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 418 (MH + ). Anal. Calcd. for C 25 H 27 N 3 O 3 : C, 71.92; H, 6.52; N, 10.06%. Found: C, 71.99; H, 6.69; N, 10.12%. N-{3-[(3,4-dimethoxybenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (26d). Compound 26d was obtained as pale brown solid, starting from acid 10c and 3-[(3,4- dimethoxybenzyl)oxy]aniline, following the general procedure reported for compound 13a (30% yield). Mp C. IR (KBr) 3444, 2925, 1664, 1602, 1206, 1017, 998, 874, 853, 805 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.94 (s, 1 H), 8.12 (d, J = 6.0 Hz, 2 H), (m, 4 H), (m, 2 H), 6.81 (d, J = 6.0 Hz, 2 H), 6.65 (m, 1 H), 5.04 (s, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.94 (m, 2 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 463 (MH + ). Anal. Calcd. for C 26 H 29 N 3 O 4 : C, 69.78; H, 5.84; N, 9.74%. Found: C, 69.82; H, 6.01; N, 9.82%. N-{3-[(3,5-dimethoxybenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (26e). Compound 26e was obtained as pale brown solid, starting from acid 10c and 3-[(3,5- dimethoxybenzyl)oxy]aniline, following the general procedure reported for compound 13a (30% yield). Mp C. IR (KBr) 3434, 1667, 1602, 1448, 1206, 1156, 1033, 998, 830, 804 cm -1 ; 1 H 9

10 NMR (300 MHz, DMSO-d 6 ) δ 9.95 (s, 1 H), 8.13 (m, 2 H), 7.41 (m, 1 H), (m, 4 H), 6.82 (m, 3 H), 6.67 (d, J = 8.0 Hz, 1 H), 5.08 (s, 2 H), 4.00 (s, 3 H), 3.98 (s, 3 H), 3.96 (d, J = 13.0 Hz, 2 H), 2.93 (d, J = 12.0 Hz, 1 H), 2.89 (d, J = 11.0 Hz, 1 H), (m, 1 H), (m, 2H), (m, 2H). ESIMS m/z 463 (MH + ). Anal. Calcd. for C 26 H 29 N 3 O 4 : C, 69.78; H, 5.84; N, 9.74%. Found: C, 69.88; H, 5.95; N, 9.79%. N-[3-(1,3-benzodioxol-5-ylmethoxy)phenyl]-1-pyridin-4-ylpiperidine-4-carboxamide (26f) Compound 26f was obtained as a pale brown solid, starting from acid 10c and 3-(1,3-benzodioxol- 5-ylmethoxy)aniline, following the general procedure reported for compound 13a (45% yield). Mp C. IR (KBr) 3429, 2925, 1666, 1604, 1253, 1208, 1102, 1037, 1027, 926, 805 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.91 (s, 1 H), 8.11 (d, 2 H), 7.35 (s, 1 H), (m, 2 H), 6.96 (s, 1 H), 6.88 (s, 2 H), 6.80 (d, J = 6.0, 2 H), 6.64 (d, J = 6.0, 1 H), 5.98 (s, 2 H), 4.91 (s, 2 H), 3.96 (d, J = 12.0, 2 H), (t, J = 12.0, 2 H), (t, J = 13.0, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 463 (MH + ). Anal. Calcd. for C 25 H 25 N 3 O 4 : C, 69.59; H, 5.84; N, 9.74%. Found: C, 69.62; H, 5.90; N, 9.88%. N-{2-[(3-fluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (27). Compound 27 was obtained as brown solid, starting from acid 10c and 2-[(3- fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (63% yield). Mp C. IR (KBr) 1633, 1524, 1254, 1084, 748 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.90 (s, 1 H), 8.29 (d, J = 5.0 Hz, 2 H), 7.50 (d, J = 7.0 Hz, 1 H), (m, 2 H), (m, 2 H), 6.75 (d, J = 5.0 Hz, 2 H), (m, 3 H), 5.00 (s, 2 H), 3.98 (d, J = 13.0 Hz, 2 H), 3.30 (d, J = 12.0 Hz, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.15; H, 6.10; N, 10.37%. N-{4-[(3-fluorobenzyl)oxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (28). Compound 28 was obtained as a brown solid, starting from acid 10c and 4-[(3- fluorobenzyl)oxy]aniline, following the general procedure reported for compound 13a (45% yield). Mp C. IR (KBr) 1601, 1510, 1449, 1232, 1083, 830 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.91 (s, 1 H), 8.15 (m, 2 H), 7.5 (d, J = 8.0 Hz, 2 H ), (m, 2 H), (m, 2 H), 6.82 (m, 2 H), 6.75 (d, J = 8.0 Hz, 2 H), 5.05 (s, 2 H), 3.98 (d, J = 13.0 Hz, 2 H), 2.93 (d, J= 12.0 Hz, 1 H), 2.89 (d, J = 11.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.15; H, 6.12; N, 10.45%. 10

11 N-{3-[2-(4-fluorophenyl)ethoxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (32). Compound 32a was obtained as brown solid, starting from acid 10c and 3-[(4- fluorophenyl)ethoxy]aniline, following the general procedure reported for compound 13a (32% yield). Mp C. IR (KBr) 3446, 2949, 1667, 1605, 1510, 1450, 1213, 1155, 998, 808 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.88 (s, 1 H), 8.11 (d, J = 5.0 Hz, 2 H), (m, 3 H), (m, 4 H), 6.81 (d, J = 5.0 Hz, 2 H), 6.60 (d, J = 3.0 Hz, 1 H), 4.08 (t, J = 6.5 Hz, 2 H), 3.94 (d, J = 12.0 Hz, 2 H), 2.99 (t, J = 6.5 Hz, 2 H) 2.87 (d, J = 12.0 Hz, 1 H), 2.84 (d, J = 12.0 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 420 (MH + ). Anal. Calcd. for C 25 H 26 N 3 O 2 F: C, 71.58; H, 6.25; N, %. Found: C, 71.72; H, 6.22; N, 10.12%. N-{3-[2-(3-fluorophenyl)ethoxy]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (32b). Compound 32b was obtained as brown solid, starting from acid 10c and 3-[(3- fluorophenyl)ethoxy]aniline, following the general procedure reported for compound 13a (32% yield). Mp C. IR (KBr) 1666, 1605, 1556, 1449, 1212, 1083, 1046, 998, 881, 807, 782, 689 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.89 (br, 1 H), 8.12 (d, J = 6.5 Hz, 2 H), (m, 2 H), (m, 5 H), 6.83 (d, J = 6.5 Hz, 2 H), 6.59 (d, J = 8.0 Hz, 1 H), 4.12 (t, J = 7.0 Hz, 2 H), 3.98 (d, J = 13.5 Hz, 2 H), 3.02 (t, J = 6.5 Hz, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 420 (MH + ). Anal. Calcd. for C 25 H 26 N 3 O 2 F: C, 71.58; H, 6.25; N, %. Found: C, 71.65; H, 6.31; N, 10.18%. N-{3-[(4-fluorophenoxy)methyl]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (33a). Compound 33a was obtained as brown solid, starting from acid 10c and 3-[(4- fluorophenoxy)methyl]aniline, following the general procedure reported for compound 13a (70% yield). Mp C. IR (KBr) 3450, 2926, 1665, 1600, 1201, 996, 826, 806, 692 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.98 (s,1 H), 8.13 (s, 1 H), (m, 1 H), (m, 5 H), (m, 2 H), (m, 2 H), (m, 2 H), (m, 2 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.12; H, 5.99; N, 10.40%. N-{3-[(3-fluorophenoxy)methyl]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (33b). Compound 33b was obtained as brown solid, starting from acid 10c and 3-[(3- fluorophenoxy)methyl]aniline, following the general procedure reported for compound 13a (27% yield). Mp C. IR (KBr) 3466, 1662, 1606, 1446, 1132, 1026, 997, 807 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.27 (d, J = 6.5 Hz, 2 H), 7.63 (br, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 2 H), (m, 3 H), 6.74 (d, J = 8.0 Hz, 1 H), (m, 3 H), 5.04 (s, 2 H),

12 (d, J = 14.0 Hz, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 406 (MH + ). Anal. Calcd. for C 24 H 24 N 3 O 2 F: C, 71.09; H, 5.97; N, 10.36%. Found: C, 71.22; H, 5.92; N, 10.42%. N-{3-[2-(4-fluorophenyl)ethyl]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (34a) Compound 34b was obtained as brown solid, starting from acid 10c and 3-[(4- fluorophenyl)ethyl]aniline, following the general procedure reported for compound 13a (50% yield). Mp C. IR (KBr) 3437, 1686, 1600, 1509, 1447, 1220, 1201, 997, 820 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.36 (s,1 H), (m, 3 H), 7.84 (d, J = 9.0 Hz 1 H), 7.59 (d, J = 8.0 Hz, 1 H), (m, 2 H), 7.37 (t, J = 8.0 Hz 1 H), 7.07 (t, J = 9.0 Hz, 2 H), 6.80 (d, J = 7.0 Hz, 2 H), 4.59 (d, J = 6.0 Hz, 4 H), 4.03 (d, J = 13.0 Hz, 2 H), 2.94 (t, J = 13.0 Hz, 2 H), (m,1 H), (m, 2 H), (m, 2 H). ESIMS m/z 404 (MH + ). Anal. Calcd. for C 25 H 26 N 3 OF: C, 74.42; H, 6.49; N, %. Found: C, 74.50; H, 6.52; N, 10.49%. N-{3-[2-(3-fluorophenyl)ethyl]phenyl}-1-pyridin-4-ylpiperidine-4-carboxamide (34b). Compound 34b was obtained as brown solid, starting from acid 10c and 3-[(3- fluorophenyl)ethyl]aniline, following the general procedure reported for compound 13a (35% yield). Mp C. IR (KBr) 1664, 1605, 1561, 1487, 1448, 997, 791 cm -1 ; 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.88 (s, 1 H), 8.12 (d, J = 5.0 Hz, 2 H), 7.49 (s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), (m, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), (m, 4 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.81 (d, J = 5.0 Hz, 1 H), 3.97 (d, J = 13.0 Hz, 2 H), (m, 6 H), (m, 1 H), (m, 2 H), (m, 2 H). ESIMS m/z 404 (MH + ). Anal. Calcd. for C 25 H 26 N 3 OF: C, 74.42; H, 6.49; N, %. Found: C, 74.49; H, 6.52; N, %. 12

13 X-ray crystal data of 13b The x-ray crystal structure of compound 13b was solved by direct methods using SIR2011 and refined by SHELXL-97. Difference-Fourier map peaks around carbon, nitrogen, and oxygen atoms have been attributed to hydrogen atoms. B-thermal factors have been anisotropically and isotropically refined for no-hydrogen and hydrogen atoms, respectively. The structural solution of 13b (crystallographic, data collection, and refining parameters are reported below in Tables S1, S2, and S3, respectively) shows an asymmetric unit containing only one molecule of compound 13b and an atom of oxygen. The oxygen atom could belong to the molecule of MeOH used as the crystallization solvent. Carbon atom was not unambiguously detected; however, three poor electron-density peaks surrounding the oxygen suggests the presence of a light atom, like carbon bound to the oxygen atom, that assumes different position in each cell. The architecture of the crystal structure (Figure S1) is mainly determined by intermolecular π-π stacking and H-bond interactions, similar in physicochemical nature to those suggested by thrombin-ligand docking calculations. Each 13b molecule turns its 3-F-Ph moiety towards that of another 13b molecule, thereby achieving a parallel-displaced configuration that usually occurs in π- π stacking. A second π-π stacking in parallel-displaced configuration between the pyridyl groups stacks up the molecules along the a axis. Notably, the N atom of the pyridine portion forms a triangular-shaped H-bond network involving amide CO and NH of two symmetry-related molecules with the O atom of a MeOH molecule, located at the centre of the triangle, that mediates the H-bond network (Figure S2). The crystal structure also shows that 13b interacts with two symmetry-related molecules through a CH π interaction between CH 2 of the 3-F-benzyl group and the central phenyl moiety. 13

14 Table S1. Crystallographic parameters for the compound 13b crystal structure. Formula C 24 H 24 N 3 O 2 F Crystal system Triclinic Space group P -1 Space group number 2 a [Å] 7.44(4) b [Å] 10.0(3) c [Å] 15.12(3) α [Å] 98.90(14) β [Å] (14) γ [Å] 98.80(18) V [Å 3 ] 1072(33) Z 2 µ [mm -1 ] F (000) 454 Crystal size [mm] Table S2. Data collection parameters for the crystal structure of compound 13b. Temperature [K] 293(2) λ [Å] θ range [ ] Ranges N(hkl) total 4033 N(hkl) unique 2017 N(hkl) used [I obs >2σ(I obs )] 441 Resolution [Å] 0.80 Table S3. Refining parameters for the crystal structure of compound 13b. Number of refined parameters 267 R[I obs >2σ(I obs )] R1 = R (all reflections included) R1 = ; wr2 = GoF

15 Figure S1. Crystal packing of 13b (axes a, red, b, green, and c, blue, of the unit cell are shown). C atoms are shown in gray color, O atoms in red color, N atoms in light blue color, H atoms in white color, and fluorine atoms in yellow color. Figure S2. H-bond network between the pyridine N atom, amide CO and NH of two symmetryrelated molecules and the O atom attributed to the MeOH molecule. Distance between H-bond donor and acceptor atoms are shown. C atoms are shown in gray color, O atoms in red color, N atoms in light blue color, and H atoms in white color. 15